Abstract
On September 22, 2021, the Food and Drug Administration approved ruxolitinib for the treatment of chronic graft-versus-host disease (cGVHD) after the failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-365 (REACH-3; CINC424D2301; NCT03112603), a randomized, open-label, multicenter trial of ruxolitinib in comparison to best available therapy (BAT) for the treatment of corticosteroid-refractory cGVHD occurring after the allogeneic hematopoietic stem cell transplantation. A total of 329 patients were randomized 1:1 to receive either ruxolitinib 10 mg twice daily (n = 165) or BAT (n = 164). BAT was selected by the investigator prior to randomization. The overall response rate through Cycle 7 Day 1 was 70% (95% CI, 63-77) in the ruxolitinib arm, and 57% (95% CI, 49-65) in the BAT arm. The median duration of response, calculated from first response to progression, death, or initiation of new systemic therapies for cGVHD, was 4.2 months (95% CI, 3.2-6.7) for the ruxolitinib arm and 2.1 months (95% CI, 1.6-3.2) for the BAT arm; and the median time from first response to death or initiation of new systemic therapies for cGVHD was 25 months (95% CI, 16.8-not estimable) for the ruxolitinib arm and 5.6 months (95% CI, 4.1-7.8) for the BAT arm. Common adverse reactions included anemia, thrombocytopenia, and infections. Given the observed response rate with durability, the clinical benefit of ruxolitinib appears to outweigh the risks of treatment for cGVHD after the failure of one or two lines of systemic therapy.
Keywords: ruxolitinib, graft-versus-host disease, hematopoietic stem cell transplantation
FDA approval of ruxolitinib provided a treatment option for patients with chronic graft-versus-host disease who do not respond to one or two lines of systemic therapy. This article summarizes the FDA review of ruxolitinib based on the REACH-3 Study.
Implications for Practice.
Using ruxolitinib for the treatment of chronic graft-versus-host disease (cGVHD) after the failure of one or two lines of systemic therapy, responses were observed in 64%-70%, with complete response in 3%-8%. The approval of ruxolitinib provides a treatment option for adult and pediatric patients 12 years and older with cGVHD who do not respond to one or two lines of systemic therapy.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with hematological malignancies. Chronic graft-versus-host disease (cGVHD) is a multisystem inflammatory disorder that occurs in approximately 40% of patients within the first year after the allogeneic HSCT.1-3 Steroids have been the standard first-line treatment for cGVHD with or without a calcineurin inhibitor, depending on the severity of the disease.4,5 Ibrutinib and belumosudil are approved treatments of refractory cGVHD but approximately 50% of the patients with cGVHD require 3 or more lines of therapies.6
Ruxolitinib (Jakafi) is an inhibitor of the Janus-associated kinases JAK1 and JAK2, regulators of a signaling pathway implicated in the development and maintenance of cGVHD.7 In an animal model of cutaneous cGVHD, ruxolitinib reduced the clinical and histological abnormalities.8 In published clinical case series and retrospective reviews, complete response (CR) rates of 4%-49% and overall response rates (ORRs) of 47%-91% were reported using ruxolitinib for cGVHD refractory to steroids alone or in addition to other immunosuppressive drugs.9-30 In 2019, ruxolitinib was approved for the treatment of steroid-refractory acute GVHD based on the REACH-1 Study (Table 1). Herein we provide a summary of the Food and Drug Administration (FDA)’s review31 of ruxolitinib for the treatment of cGVHD after the failure of one or two lines of systemic therapy based on the REACH-3 Study.
Table 1.
Ruxolitinib background information.
| Structure | • (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate |
| Mechanism of action | • Inhibits JAK1 and JAK2, thereby blocking the action of cytokine signaling through the JAK-STAT pathway. |
| Prior approvals | • Treatment of patients with: – Intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera in adults (2011). – Polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea in adults (2014). – Steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older (2019). |
| New indication | • Treatment of chronic graft-versus-host disease (cGVHD) after failure of one or 2 lines of systemic therapy in adult and pediatric patients 12 years and older. |
| Pharmacokinetics | • Renal clearance of ruxolitinib in patients with GVHD was approximately 50% of that observed in patients with myelofibrosis. |
Trial Design
The REACH-3 Study (CINC424D2301; INCB 18424-365; NCT03112603) was a randomized, open-label, multicenter study of ruxolitinib for the treatment of corticosteroid-refractory cGVHD occurring after the allogeneic HSCT.32 Eligible patients were 12 years of age or older with moderate or severe cGVHD as defined by NIH consensus criteria33 and required additional therapy after the failure of corticosteroid therapy and no more than one additional salvage treatment. Patients were to be excluded if they had an absolute neutrophil count ≤1 Gi/L, platelet count ≤25 Gi/L, estimated creatinine clearance <30 mL/minute, progressive onset cGVHD, oxygen saturation <90%, total bilirubin >2 mg/dL, or diarrhea due to GVHD.
Patients were randomized 1:1 to receive either ruxolitinib or the best available therapy (BAT) in 28-day cycles. On the investigational arm, patients were treated with ruxolitinib 10 mg twice daily. On the BAT arm, treatment options included extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, mammalian target of rapamycin (mTOR) inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib. The BAT for an individual patient was selected prior to randomization. On Cycle 7 Day 1 and thereafter, patients randomized to BAT could cross over to ruxolitinib if they had disease progression, mixed response, unchanged response, cGVHD flare, or toxicity to BAT. All patients also received standard supportive care, including anti-infective medications. GVHD prophylaxis and cGVHD treatment medications initiated before randomization, including systemic corticosteroids, calcineurin inhibitors, and topical or inhaled corticosteroid therapy, were allowed to be continued per institutional guidelines.
Randomization was stratified by cGVHD severity (moderate vs. severe). The primary objective was to compare the efficacy of ruxolitinib vs investigator’s choice of BAT assessed by the endpoint of overall response (OR), consisting of CR or partial response (PR), as determined by the investigator at the Cycle 7 Day 1 visit according to the 2014 NIH consensus criteria.34 The difference in ORR between the two treatments was to be compared using the Cochran–Mantel–Haenszel test stratified by the cGVHD severity. It was hypothesized that the BAT Cycle 7 Day 1 ORR ranged from 58% to 66%, and the targeted odds ratios were 2.35 and 2.5, respectively. A sample size of 324 patients was considered adequate to detect the targeted odds ratio with 90% power at the one-sided 2.5% level of significance. An interim analysis was planned to occur when 194 patients (60% of the accrual target) were evaluable for the primary endpoint of ORR at Cycle 7 Day 1 or discontinued earlier, and the final analysis was to occur when all patients had completed the Cycle 7 Day 1 visit or discontinued earlier. A ≥7-point reduction in cGVHD total symptom score (TSS) (see Section 7.2.6 of the protocol in the Supplementary Materials for Reference32) at the Cycle 7 Day 1 visit was the key secondary endpoint according to planned hierarchical testing, and ORR by Cycle 7 Day 1 was listed as an additional endpoint.
Efficacy
There were 329 patients randomized, 165 to ruxolitinib and 164 to BAT. Table 2 shows the demographics and baseline disease characteristics of the randomized population. The median age was 49 years; 3% were <17 years old, and 15% were >65 years old. Males accounted for 61% of the patients. The study population was 75% White, 16% Asian, 8% of other races, and 8% Hispanic. cGVHD was severe for 50%; 95% after the failure of one line of therapy and 4% after the failure of 2 lines of therapy. The median cGVHD TSS at baseline was 18.6. The demographics and baseline disease characteristics were largely balanced between arms. The majority of patients were treated in Europe or Australia; only 10% of the study population was from the US.
Table 2.
Characteristics of the REACH-3 primary efficacy population.
| Ruxolitinib treatment population (N = 165) | Best available therapy population (N = 164) | |
|---|---|---|
| Median age | 49 years | 50 years |
| (range) | (13-73 years) | (12-76 years) |
| Age group, n (%) | ||
| 12-<17 years | 4 (2%) | 6 (4%) |
| 17-<65 years | 140 (85% | 129 (79%) |
| ≥65 years | 21 (13%) | 29 (18%) |
| Sex, n (%) | ||
| Male | 109 (66%) | 92 (56%) |
| Female | 56 (34%) | 72 (44%) |
| Race, n (%) | ||
| White | 116 (70%) | 132 (81%) |
| Asian | 33 (20%) | 21 (13%) |
| Black | 2 (1%) | 0 0 |
| Other or unknown | 14 (8%) | 11 (7%) |
| Ethnicity, n (%) | ||
| Hispanic/Latino | 13 (8%) | 13 (8%) |
| Not Hispanic/Latino | 118 (72%) | 115 (70%) |
| Not Reported | 26 (16%) | 25 (15%) |
| Unknown | 8 (5%) | 11 (7%) |
| Prior therapy for cGVHD, n (%) | ||
| No prior treatment for cGVHD | 2 (1%) | 1 (1%) |
| After failure of first-line steroids alone | 115 (70%) | 125 (76%) |
| After failure of first-line combination including steroids | 42 (25%) | 30 (18%) |
| After failure of 2 lines of therapy | 6 (4%) | 8 (5%) |
| ≥4 organs involved, n (%) | 67 (41%) | 63 (38%) |
| Severe cGVHD, n (%) | 86 (52%) | 79 (48%) |
| Median cGVHD total symptom score (range) | 19 (0-80) | 18 (1-54) |
| Median corticosteroid dose at baseline (range) (PE mg/kg)a | 0.29 (PE mg/kg)a (0.01-1.81) |
0.26 (PE mg/kg)a (0.06-1.21) |
| Median time from cGVHD diagnosis to randomization (range) | 174 days (7-2017 days) |
150 days (10-947 days) |
Prednisone equivalent milligrams/kilogram.
Abbreviation: cGVHD, chronic graft-versus-host disease.
Using Investigator-determined responses, the Applicant reported that the comparison of ORR at the Cycle 7 Day 1 visit crossed the efficacy boundary at the interim analysis and at the final analysis.32 FDA adjudicated all responses using all available raw data for the components of the response criteria for the efficacy analyses (see Supplementary Table S1). FDA calculated an ORR at the Cycle 7 Day 1 Visit of 42% versus 24% for the ruxolitinib and BAT arms, respectively, with an odds ratio of 2.4 (95% CI, 1.4-3.9), confirming that the study was positive in accordance with the Statistical Analysis Plan.
FDA considers a CR or PR at any time through Cycle 7 Day 1 rather than only at the Cycle 7 Day 1 Visit to be representative of a clinically meaningful response. The FDA-adjudicated ORR through Cycle 7 Day 1 was 70% (95% CI, 63-77) in the ruxolitinib arm and 57% (95% CI, 49-65) in the BAT arm with a risk difference of 13% (95% CI, 3-23). Since the analysis of this endpoint was not alpha-controlled, no P-value is displayed (Table 3). The median time to first response in the responders was 3 weeks (range: 2-24) for the ruxolitinib arm and 4 weeks (range: 2-25) for the BAT arm. The median duration of response (DOR), calculated from first response to progression, death, or new systemic therapies for cGVHD, was 4.2 months (95% CI, 3.2-6.7) for the ruxolitinib arm and 2.1 months (95% CI, 1.6-3.2) for the BAT arm; and the median time from first response to death or new systemic therapies for cGVHD was 25 months (95% CI, 16.8-NE) for the ruxolitinib arm and 5.6 months (95% CI, 4.1-7.8) for the BAT arm (Table 3).
Table 3.
Responses through Cycle 7 Day 1 in the REACH-3 primary efficacy populations.
| Ruxolitinib treatment population (N = 165) |
Best available therapy population (N = 164) |
|
|---|---|---|
| Overall response, n (%)a | 116 (70%) | 94 (57%) |
| (95% CI)b | (63%, 77%) | (49%, 65%) |
| CR, n (%) | 14 (8%) | 8 (5%) |
| PR, n (%) | 102 (62%) | 86 (52%) |
| Median duration of responsec | 4.2 months | 2.1 months |
| (95% CI) | (3.2 months, 6.7 months) | (1.6 months, 3.2 months) |
| Median time to death or new therapy | 25 months | 4.2 months |
| (95% CI) | (16.8 months, NE) | (4.1 months, 7.8 months) |
| ≥7-point decrease in the cGVHD total symptom score | 66 (40%) | 47 (29%) |
| (95% CI) | (32%, 48%) | (22%, 36%) |
Abbreviations: cGVHD, chronic graft-versus-host disease; CI, confidence interval; CR, complete response; NE, not estimable; PR, partial response
FDA-adjudicated response. Overall response includes CR or PR according to the 2014 NIH response criteria.
95% CI of Overall Response Rate is estimated using Clopper-Pearson method.
Duration of response is the interval from onset of first response (CR or PR) by Cycle 7 Day 1 to organ-level progression, death, or new systemic therapy.
Since the randomized population included few patients after the failure of 2 lines of therapy, additional information regarding efficacy in this subgroup was pursued in the crossover population. Of the 61 patients after the failure of BAT and one line of therapy prior to BAT (after the failure of 2 lines of therapy in total) and then crossed over to ruxolitinib, an OR through Cycle 7 Day 1 was achieved by 39 (ORR 64% [95% CI, 51-76]), including 2 CRs and 37 PRs. These results supported the use of ruxolitinib for patients after the failure of 2 lines of therapy.
Responses were observed across all demographic and disease-related characteristics (see Supplementary Table S2). It was noted however that only 10% of the trial participants were from the US. To assess the applicability of the trial results to the US population, ORR was evaluated in the subgroup of patients from the US in the randomized patients and in the subgroup of patients after the failure of BAT with ibrutinib (currently available therapy in the US) who then crossed over to ruxolitinib. Of the 34 patients enrolled in the US, an OR by Cycle 7 Day 1 was achieved by 7/14 (50%) patients on the ruxolitinib arm and 7/13 (54%) on the BAT arm. In the crossover population, an OR by Cycle 7 Day 1 was achieved by 6/10 (60%) patients after the failure of ibrutinib as BAT. These results supported the applicability of REACH-3 to the US population.
A response in cGVHD TSS on Cycle 7 Day 1 was a key secondary endpoint. However, no data were submitted to substantiate the meaningfulness of this measure at the arbitrary time point of the Cycle 7 Day 1 Visit. FDA conducted an exploratory analysis of patient-reported symptom severity which showed at least a 7-point decrease in the cGVHD TSS at any time through Cycle 7 Day 1 in 66 (40%; 95% CI, 32-48) patients in the ruxolitinib arm and 47 (29%; 95% CI, 22-36) patients in the BAT arm (Table 3). As this analysis is exploratory, no P-value is displayed.
Safety
Safety was evaluated in the 165 patients treated with ruxolitinib and the 158 patients treated with BAT following randomization on the REACH-3 Study. Additionally, 65 patients crossed over from BAT to treatment with ruxolitinib, for a total of 230 patients treated with ruxolitinib at any time on study. The median duration of ruxolitinib exposure was 49.7 (range, 0.7-144.9 weeks) among the 230 patients treated with ruxolitinib; 109 (47%) patients were on ruxolitinib for at least 1 year.
Among all 230 ruxolitinib-treated patients, there were 5 fatal adverse reactions to ruxolitinib, including one from toxic epidermal necrolysis and 4 from neutropenia, anemia, and/or thrombocytopenia. An adverse reaction resulting in ruxolitinib discontinuation occurred at any time on study in 18% of the 230 ruxolitinib-treated patients, an adverse reaction resulting in dose modification occurred in 27%, and an adverse reaction resulting in treatment interruption occurred in 23%. The most common nonlaboratory Grade ≥3 adverse reactions were infections (pathogen not specified) (20%) and viral infection (6%) (see Supplementary Table S4); the most common Grade ≥3 laboratory abnormalities were thrombocytopenia (11%), neutropenia (11%), anemia (9%), elevated lipase (9%), gamma-glutamyl transferase increased (9%), and elevated amylase (6%) (see Supplementary Table S5).
Since crossover was allowed following Cycle 7 Day 1, the display of safety results by the study arm is limited to data through Cycle 7 Day 1. Tables 4 and 5 show the nonlaboratory adverse reactions and selected laboratory abnormalities, respectively, occurring only through Cycle 7 Day 1 by study arm in REACH-3 for the 165 patients treated with ruxolitinib and the 158 patients treated with BAT following randomization on the REACH-3 Study.
Table 4.
Nonlaboratory adverse reactions occurring through Cycle 7 Day 1 of randomized treatment in the REACH-3 safety population.
| Adverse reactionsb | Ruxolitinib (N = 165) |
Best available therapy (N = 158) |
||
|---|---|---|---|---|
| All gradesa (%) |
Grade ≥3 (%) | All grades (%) | Grade ≥3 (%) | |
| Infections and infestations | ||||
| Infections (pathogen not specified) | 45 | 15 | 44 | 16 |
| Viral infections | 28 | 5 | 23 | 5 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain | 18 | 1 | 13 | 0 |
| General disorders and administration site conditions | ||||
| Pyrexia | 16 | 2 | 9 | 1 |
| Fatigue | 13 | 1 | 10 | 2 |
| Edema | 10 | 1 | 12 | 1 |
| Vascular disorders | ||||
| Hypertension | 16 | 5 | 13 | 7 |
| Hemorrhage | 12 | 2 | 15 | 2 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Cough | 13 | 0 | 8 | 0 |
| Dyspnea | 11 | 1 | 8 | 1 |
| Gastrointestinal disorders | ||||
| Nausea | 12 | 0 | 13 | 2 |
| Diarrhea | 10 | 1 | 13 | 1 |
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
Includes grouped terms (see Supplementary Table S2). Limited to adverse reactions with all-grade incidence ≥10%.
Table 5.
Selected laboratory abnormalities occurring up to Cycle 7 Day 1 of randomized treatment in the REACH-3 safety population.
| Laboratory test | Ruxolitinib (N = 165) |
Best available therapy (N = 158) |
||
|---|---|---|---|---|
| All gradesa,b (%) | Grade ≥3 (%) | All grades (%) | Grade ≥3 (%) | |
| Hematology | ||||
| Anemia | 82 | 13 | 75 | 8 |
| Thrombocytopenia | 58 | 20 | 54 | 17 |
| Neutropenia | 27 | 12 | 23 | 9 |
| Chemistry | ||||
| Hypercholesterolemia | 88 | 10 | 85 | 8 |
| Gamma glutamyl transferase increased | 81 | 42 | 75 | 38 |
| Elevated AST | 65 | 5 | 54 | 6 |
| Elevated ALT | 73 | 11 | 71 | 16 |
| Creatinine increased | 47 | 1 | 40 | 2 |
| Elevated lipase | 38 | 12 | 30 | 9 |
| Elevated amylase | 35 | 8 | 25 | 4 |
Presented values are worst grade values regardless of baseline.
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
The main adverse events of special interest were infection, bleeding, and thrombosis. An infection of any type was reported in 58% of the 230 ruxolitinib-treated patients, and the infection was Grades 3-5 in 14%. Supplementary Table S6 shows the incidence of all-grade and Grades ≥3 infections by pathogen group. The most common types of infections were lower respiratory tract infections (23%), upper respiratory tract infections (22%), urinary tract infections (9%), influenza viral infections (8%), cytomegaloviral infections (7%), eye and eyelid infections (7%), herpes viral infections (6%), polyomavirus infections (6%), and Epstein-Barr viral infections (5%). Supplementary Table S6 also shows the incidences of infections by the study arm through Cycle 7 Day 1. A bleeding event was reported in 29 (13%) ruxolitinib-treated patients, most commonly epistaxis (3%). Thrombosis was reported in 10 (4%), most commonly, pulmonary embolism (2%) and peripheral venous thrombosis (2%).
Clinical Pharmacology
The REACH-3 Study used a starting dose of ruxolitinib of 10 mg twice daily. There were no dose-ranging studies; the starting dose was based on published off-label experience.9,11 By Cycle 7 Day 1, the relative dose intensity for ruxolitinib was < 80% for 33% of the patients. In the exposure-response analyses using data from patients in REACH-3, there were trends for increasing risk of Grade ≥3 anemia and Grade ≥3 thrombocytopenia with increasing exposure, but no relationship between exposure and ORR or CR by Cycle 7 Day 1 (see Supplementary Fig. S1).
Population pharmacokinetics (PK) analyses using data from patients in the REACH-1 (NCT02953678),35 REACH-2 (NCT02913261),36 and REACH-3 studies showed no clinically relevant differences in ruxolitinib PK with regard to age, race, sex, or weight were observed. The apparent clearance of ruxolitinib was 9.7 L/hr, which was approximately 50% lower than that reported for patients with myelofibrosis, and the mean elimination half-life was approximately 3 h.37 The number of patients with Score 3 cGVHD liver involvement was too small to determine the effect of high-score liver cGVHD on the PK of ruxolitinib, but Score 1 or 2 cGVHD liver involvement had no clinically relevant effect.
Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. Population PK analysis indicated that there was no significant effect of strong CYP3A inhibitors on the PK of ruxolitinib in patients with cGVHD. Co-administration of fluconazole (moderate CYP3A and CYP2C9 inhibitor) 100 -400 mg total daily dose resulted in about a 50% decrease in the apparent clearance of ruxolitinib in patients with cGVHD. Table 6 shows the recommended dose modifications for patients taking concomitant CYP3A4 inhibitors and for those with organ impairment.
Table 6.
Recommended ruxolitinib starting dose for patients with cGVHD.
| Setting | Ruxolitinib Dose |
|---|---|
| Usual starting dose | 10 mg twice daily |
| Modifications for use with CYP3A4 inhibitors | |
| Fluconazole doses of less than or equal to 200 mg | 5 mg twice daily |
| Other CYP3A4 inhibitors | Monitor blood counts more frequently for toxicity and modify the ruxolitinib dosage for adverse reactions if they occur |
| Modification for renal impairment | |
| Moderate (CLcr 30 to 59 mL/minute) or severe (CLcr 15 to 29 mL/minute) | 5 mg twice daily |
| ESRD (CLcr <15 mL/minute) on dialysis | 10 mg once after dialysis session |
| Modification for hepatic disease | |
| Mild, moderate, or severe based on NCI criteria without liver GVHD | No dose adjustment |
| Score 1 or 2 liver cGVHD | No dose adjustment |
| Score 3 liver cGVHD | Monitor blood counts more frequently for toxicity and modify the ruxolitinib dosage for adverse reactions if they occur |
Adapted from the US Prescribing Information dated September 2021.
Abbreviations: cGVHD, chronic graft-versus-host disease; CLCr, creatinine clearance.
Regulatory Insights
The activity of ruxolitinib is well-established for the treatment of select patients with acute GVHD, myelofibrosis, and polycythemia vera. The REACH-3 Study was the first prospective trial of ruxolitinib for the treatment of cGVHD. Table 7 presents the FDA benefit-risk assessment for ruxolitinib for the treatment of cGVHD. FDA considered the following results to represent substantial evidence of the effectiveness of ruxolitinib in this indication: the 70% ORR by Cycle 7 Day 1 with a lower bound of 63% with substantial durability, the consistency in numerical improvement in comparison to BAT across efficacy outcomes, the observation of a treatment effect across subgroups, the finding of at least a 7-point reduction in cGVHD TSS in 40% of patients, and the supporting results from the crossover population were considered.
Table 7.
FDA benefit-risk assessment for ruxolitinib for the treatment of cGVHD.
| Parameter | Summary |
|---|---|
| Current treatment options | • Ibrutinib and belumosudil are approved for the treatment of cGVHD, but the duration of response with these agents are relatively short. • More than half of the patients with cGVHD require 3 or more lines of treatment. • There is a need for new treatments for cGVHD. |
| Benefit | • In the randomized REACH-3 Study for treatment of cGVHD, the ORR by C7D1 was 70% (95% CI: 63%, 77%) in the ruxolitinib arm and 57% (95% CI: 49%, 65%) in the BAT arm with a risk difference of 13% (95% CI: 2.6%, 23.1%), largely for patients after failure of one line of therapy. The median duration of response was 4.2 months for ruxolitinib and 2.1 months for BAT, and the median time to new therapy or death was 25 months for ruxolitinib and 5.6 months for BAT. • In the crossover population, the ORR by C7D1 was 66% (95% CI: 53%, 77%) for the patients after failure of 2 lines of therapy • A ≥7-point reduction in cGVHD TSS score by C7D1 was achieved by 40% on ruxolitinib and 29% on BAT. |
| Risks and risk management | • In the 230 patients treated with ruxolitinib, the all-grade nonlaboratory ARs in >20% were infections (pathogen not specified) and viral infection, and the grades 3-4 laboratory abnormalities in >5% were thrombocytopenia, neutropenia, anemia, elevated lipase, elevated gamma-glutamyl transferase, and elevated amylase. There were 5 fatal adverse reactions (1 toxic epidermal necrolysis and 4 from cytopenias). An adverse reaction resulting in treatment discontinuation occurred in 18%, dose modification in 27%, and treatment interruption occurred in 23%. • The clinical trial included specific monitoring and dose modifications to mitigate serious toxicities. |
| Uncertainties | • The safety profile of 10 mg twice a day (BID) appears tolerable in the short term, but additional studies are needed to establish the safety of long-term use in this population. |
| Conclusions | • The overall benefit-risk is favorable for ruxolitinib 10 mg BID for treatment of cGVHD after failure of 1 or 2 prior lines of therapy. |
Abbreviations: ARs, adverse reactions; BAT, best available therapy; C7D1, Cycle 7 Day 1; cGVHD, chronic graft-versus-host disease; CI, confidence interval; ORR, overall response rate; TSS, total symptom score.
Major strengths of the REACH-3 Study were the randomized design and the inclusion of adolescents in the trial. The latter was especially advantageous for accelerating development of this drug for pediatric use under this indication. The exclusion, however, of patients with moderate elevations of bilirubin or those with substantial hypoxemia, as may be consistent with severe cGVHD in liver or lung, was considered a weakness of the design, since then the results of the trial may not be applicable to patients with advanced cGVHD. Such patients are thought to have irreversible tissue damage that will not respond to drug that targets just inflammation, and new treatments are greatly needed for these highly morbid forms of cGVHD.
An additional weakness was the lack of dose optimization prior to the conduct of the trial. The trend in the exposure-response analyses for higher rates of key adverse reactions with higher exposures of ruxolitinib (Supplementary Fig. S1) underscores the need for precise dosing to maintain a favorable balance of risk and benefit. Indeed, one-third of the patients had a relative dose intensity of less than 80% by the end of 6 cycles of treatment with ruxolitinib.31 Nonetheless, with the recommended monitoring and dose modifications for toxicities in place, the safety profile of ruxolitinib was considered acceptable in the short term for this patient population. Additional data are needed to ensure safety of the recommended dose with long-term use in this population.
The ultimate goal for therapy of cGVHD is to re-establish tolerance and discontinue toxic drug treatment. We acknowledge, however, that the current understanding of the basic science of cGVHD is not sufficient to allow the development of an individual drug for this lofty goal. Since cGVHD is a morbid disease, FDA instead considers an objective and measurable reduction in the signs and symptoms of cGVHD as clinically meaningful at this time. To this end, FDA has accepted CR or PR (OR) by the 2014 NIH consensus criteria as the measure of response. In REACH-3, the primary endpoint was OR at the Cycle 7 Day 1 Visit. Although preliminary analyses of independent data sets have suggested that OR at 6 months of treatment correlated with overall survival, failure-free survival, or subsequent treatment change,38,39 these analyses were not performed with the statistical rigor needed to verify the 6-month timepoint as optimal for the association with longer-term outcomes. As such, FDA currently accepts a CR or PR starting at any time in the first 6 months of treatment for the assessment of effectiveness.
Additionally, to be clinically meaningful, the response should be durable. In the REACH-3 Study, the DOR was 4.2 months in ruxolitinib arm, which is somewhat short. However, the definition of DOR (Supplementary Table S1) does not take into account that cGVHD may flare and resolve without additional systemic treatment. An alternative measure of the durability of response would be the time to death or new systemic therapy. For the 116 responders in ruxolitinib arm, the median time to either death or new systemic therapy for cGVHD was 25 months. This additional measure is considered a meaningful representation of the durability of the response for cGVHD.
An improvement in a patient-reported outcomes (PROs) is also of clinical interest in patients undergoing treatment for cGVHD. In the REACH-3 Study, the cGVHD TSS was used to assess patient-reported severity of symptoms. Although the PRO tool used in the REACH-3 Study had been referred to as the modified Lee Symptom Scale (mLSS) in publications,35 the cGVHD TSS used differs from the mLSS as published by the inventor40 in that the cGVHD TSS asks about symptom severity rather than symptom bother, and it has more items on the questionnaire. In a supplementary analysis, a ≥7-point reduction in cGVHD TSS at any time through Cycle 7 Day 1 was observed for 40% of patients in the ruxolitinib arm and 29% in the BAT arm. It should be recognized that the observed cGVHD TSS analysis results from REACH-3 may be biased due to the open-label nature of the trial, and statistical significance cannot be concluded from this exploratory analysis, but given the interest from the healthcare providers and patients in PRO information, descriptive cGVHD TSS results are included in the US Prescribing Information without a formal comparison between arms.
In conclusion, given the observed response rate and durability, and with the labeling modifications in place for safety concerns, the clinical benefit of ruxolitinib outweighs the risks for the treatment of cGVHD after the failure of one or 2 lines of systemic therapy in adult and pediatric patients 12 years and older. Additional study is needed to confirm safety with long-term use.
Supplementary Material
Acknowledgments
We thank Saumya Nathan, MS and Sheila Ryan, PharmD, MPH for expert review management. This is a U.S. Government work. There are no restrictions on its use.
Contributor Information
Robert Q Le, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Xin Wang, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Hongfei Zhang, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Hongshan Li, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Donna Przepiorka, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Jonathon Vallejo, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Ruby Leong, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Lian Ma, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Kirsten B Goldberg, Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Richard Pazdur, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA; Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Marc R Theoret, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA; Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Angelo De Claro, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Funding
None declared.
Conflict of Interest
The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.
Author Contributions
Conception/design: All authors. Collection and/or assembly of data: All authors. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors.
Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.